PROJECT SUMMARY/ABSTRACT Stroke is a disease of epidemiological proportions in the industrialized world and a leading cause of long-term disabilities. One third of stroke patients maintain long-term motor deficits severe enough to be disabling, despite rehabilitative efforts. We have proposed dentate nucleus deep brain stimulation (DN-DBS) as a therapy to facilitate motor recovery for patients with chronic upper extremity hemiparesis due to ischemic stroke. Our working hypothesis is that low-frequency, DN-DBS increases excitatory dentatothalamocoritical output; thereby enhancing cerebral cortical excitability and facilitating functional reorganization in perilesional cortical areas that support further motor recovery. Our supporting data demonstrate that motor recovery facilitation can be achieved with a single electrode system in the ischemic rodent model, with those changes accompanied by sustained increments in cerebral cortical excitability in perilesional regions, perilesional reorganization of motor representation, and increased expression of markers of long-term potentiation and synaptogenesis. Our preclinical data has reached the point of human translation and, based on these data, we have obtained FDA approval for a first-in-man DN-DBS clinical trial to assess the safety and feasibility of DN-DBS for patients with persistent, moderate-to-severe upper-extremity hemiparesis secondary to middle cerebral artery ischemic stroke. The experiments proposed in the present study will build upon the opportunities provided by this clinical trial. Specifically, we will obtain and analyze behavioral and physiological data from human subjects to advance the development and evaluation of a next-generation system that will be specifically designed for post-stroke rehabilitation enhancement. These studies will be carried out by an investigative team with multiple, long-standing collaborations aimed at the development of DN-DBS technologies and treatment of motor impairments following stroke; the team spans expertise in clinical trials, neurology, neurosurgery, neurophysiology, neurorehabilitation, neuropsychology, radiology, and computational modeling. An Investigational Device Exemption with the Food and Drug Administration for the safety and feasibility trial was granted in December of 2015 and IRB approval is pending.